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1. Write to BfArM and HSM of 27 1st October 2005

Federal Institute for Drugs and Medical Devices

Kurt-Georg-Kiesinger-Allee 3 53175 Bonn

Re:. Approval of substances for intravenous infusion in humans

Here: oil-containing infusion solutions (lipid infusion solutions) for so-called parenteral nutrition

UiB: labeling / Application ban

Ladies and Gentlemen,

on the basis of findings in the context of a since 22 February 2005 by the CID office-research-driven, independent research project on the question of the use of lipid infusion solutions - especially the misuse of the patient - is sufficient reason for us to invite you to avoid damage to the noted hereinafter referred to deficiencies and hazards.

introduction, I would point you out that is unknown to me, as if the nutrient solutions for intravenous infusion substances are declared as "drug" within the meaning of the required admission tests for pharmaceutical products, ie, whether these products prior to approval of the proof of its harmlessness has been provided for the people, or if so, how this was accomplished.

According to the current drug list for Germany ( Red List 2005 ) appear in the Federal Republic of Germany under the heading infusion and standard solutions for injection under the item 2.5. Bold solutions 12 products the company Baxter, DeltaSelect, B / Braun, Fresenius Kabi and Grifols with the brand name recorded CLINOLEIC, DELTA LIPID, Intralipid, Lipofundin, LIPOVENÖS, OMEGAVEN, SALVILIPID and SOYACAL as oil emulsions for intravenous infusion.

include this infusion solutions at various compositions

as fat for intravenous nutrients

• 10% to 30% oil from soybeans (and allegedly also in olive and deep sea fishing)

as emulsifiers and stabilizers of the emulsion

• egg lecithin

• alpha-tocopherol

• glycerol

• sodium oleate

• phosphatidylcholine (phospholipids)

• sodium

and as a vehicle

• water for injections

Due to the composition of the above mentioned substances in our view, be assumed that the intravenous administration of the oil-containing emulsions in humans and mammals in the best case to health in the worst case, lead to death must.

This assumption is based on the following facts:

Due to their high surface tension of water form and natural fats (oils) do not form stable mixtures (emulsions) but separate after mixing quickly into 2 phases. The supply of non-emulsified oil as a nutrient to the blood would lead to the formation of a blood embolism (lung embolism, cerebral embolism, etc) result, which organ damage or even death of the treated patients as a consequence.

The attempt would be prepared by admixture of the surface tension-reducing emulsifiers (see above list) stable emulsions for intravenous infusion, with equal security for such patients treated similar consequences, since the emulsifiers proportional to its surface tension-reducing effect of hemolytic , ie, blood cells and capillary-depleting Durchlässigkeitserhöhende Effect in the blood plasma and would develop blood vessel endings, which would in turn lead to the formation of pulmonary edema or death due to hemolytic shock immediately after intravenous infusion.

investigations in support of this risk analysis, have been 1950-1962 in the context of the causes of deaths after use of the now withdrawn lipid infusion LIPOMUL (Upjohn) and ABBOLIPID (Abbott) performed and published.

To reveal studies of Meyer and Waltz from the year 1959 a creamy whitish change in blood plasma and the complete disruption of the blood clotting ability to Lipomul injections.

( NEUROLOGY -. Official Journal of the American Academy of Neurology, Volume IX, Jan.-Dec 1959 p. 728-740 )

Leve, GIORDANO and Spletzer found in 1961 in untersuchtem Lipomul blood after infusions also designated the "creaming" marked change in consistency of the blood plasma and precipitation of a phosphatide-containing emulsion stabilizer.

( ARCHIVES OF SURGERY, Volume 83, July-Dec. 1961, p.311-321 )

Already in 1950, described Leve, Papps, Restuccia and MULHOLLAND the surface tension reducing effect of emulsifiers to have caused the damage to the cell membranes of the capillaries of the blood vessel system, hemolysis, anemia, and pulmonary edema and caused the development of hyperlipidemia (high blood fat) and fat embolism by the shares of the emulsions.

( THE AMERICAN JOURNAL OF DIGESTIVE DISEASES, Volume 17, Number 1, January 1950, p.20-24 )

At least the occurrence of dyslipidemia and hypercholesterolemia are considered characteristic of a Verschlußikteritis in recent investigations of Hajri, FEREZOU Lutton and as usual effects of intravenous infusion of intralipid (Baxter) "means.

Under ( Biochimica et Biophysica Acta, Volume 1047 (1990) p. 121-130 )

into account the to the reasons mentioned here, we keep a ban on the substances mentioned above adequate, given the above mentioned oil-containing infusion solutions are not caused by them because of the effects on the human body can be considered as a remedy in the strict sense.

From our View, these substances for the treatment of patients who are fed only intravenously, can easily be replaced by the intravenous administration of isotonic saline solution for nutrient supply and to compensate for the lost fluid to replace one in the hospital everyday proven means of its administration have been proved to have no adverse health effects result . would

Until a decision and enforcing a ban on the production and application ensure at producers, pharmaceutical wholesalers and hospital pharmacies in the stocks or destroy, any spread or the application of the substances in non-hospital patients treated with infusion therapy excluded.

is in this context, particularly the issue of erroneous and improper use of these substances.

Assuming involve the above-described effect of funding on the human organism, it would be a declaration as fat intravenous nutrients inappropriate, wrong and misleading. The substances were not drugs or nutrients but at best classified the case as "Harmful" or "Toxic" , which would involve labeling requirement under the Hazardous Substances (see below) to themselves.

before enforcement of a ban would ensure the infusion bottles and stocks under an emergency decree to label containers with the required marks for the packaging requiring labeling of hazardous or Making of toxic substances in order to prevent potential accidental or inadvertent use in humans.

exist for this, alternatively hereby requested measure labeled "Toxic" as "harmful" or up to the enforcement of a ban and the safeguarding of the substances under the following reasons:

The occurrence of described above, adverse health effects from the intravenous infusion of the lipid infusion solutions is directly related to the infusion volume and infusion rate, ie the mixing ratio of the substances in the blood and the dilution in the same onward movement through the vascular system.

The rapid mixing of larger quantities of the infusion with the blood is assumed that irreversible damage within a short time a blood embolism or a hemolytic shock the patient and causing his death.

were allowed to Verabreichnung The lower infusion volumes over a longer period, just as life-threatening blood or organ damage (embolism, blood clotting disorders, anemia, edema, etc.) near- and are not necessarily the cause to bring the gift of lipid infusion solutions in context. is

Since the so-called parenteral nutrition , that the intravenous nutrient supply in the hospital everyday life usually practiced in patients, for whom "a generally negative trend, forecast their health" has been diagnosed (in particular because these patients "do not absorb food through the intestines more would"), so that further deterioration of their health status "anticipated by the treatment staff" will be after intravenous injection of lipid infusion solutions onset of blood, blood vessel and organ damage and their appearance on the patient visible consequences (jaundice, etc.) "regarded mostly as a sign of anyway expected deterioration," and with no relation to the administered substances to be related.

lipid infusion solutions have therefore the character of a "concealed weapon usable.

our investigations are known to result from hospitals in cases where the nursing staff lipid infusion solutions " for faster delivery from its sterile packaging containers (infusion bottle) were taken and transferred to syringes to have been ". The intravenous injection of 250 ml syringes would be then " at once by injecting the infusion fluid flow into the vein " because " the nursing staff so do not spend hours sat next to the patient could "to the substance according to the prescribed dosage regimen in the proportion slowly dropwise to make a maximum of 1-2 grams per kilogram of body weight per day in the vein.

It is up to the individual assessment of whether the death of a patient after lipid infusion dose of ignorance of the nursing staff is done on the effect of the infusion means, or whether he is regarded as a consequence of the proposed induction of death.

In conclusion, the existence of the lipid infusion solutions by

• their misleading declaration as a "culture media", by

• their application in connection with negative forecasts for the development of the health status of hospital patients and

• the apparent lack of knowledge of established before 40-50 years to settle from the physical mixing behavior of fats in resulting aqueous solutions, harmful effects

a "gray area" in the treatment of hospital patients has been created which have a linkage mechanism between diagnosis, treatment, substance administration and the occurrence of the Death of the patient generated that goes against the Hippocratic principle of the obligation to preserve life.

But it must be in the treatment of patients no automatism leading to death.

It should also be no, by the existence of lipid infusion-related solutions, almost ritualized process of getting used to a diagnosed terminal care of hospital patients.

any medical treatment, especially dealing with people who were entrusted to the staff working in hospitals or entrusted to this need, the restoration the health of these people to target.

remain Awaiting your opinion, I

Sincerely

Biol Peter Zanger
Research Director CID / CID-Verlag
Weilmünster, Thursday 27 October 2005

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Write to the HSM of 21 December 2005

Hessian Ministry of Social Affairs
The Social Security
PO Box 3140
65 021 WIESBADEN

AZ V 7 A - 181 02 13

ban initiative on oil emulsions for intravenous infusion

here: Your letter of 22 November 2005

Dear Mrs Lautenschläger

outset, I thank you for the detailed replies to my letter of 27 October 2005 and for Your search for information about the approval procedure of the lipid infusion solutions including in the drug database, AMIS.

based in fact, as you noted correctly, my objections to the declaration of the oil emulsions as a "culture media" in scientific publications from 1950 to 1962. The detailed investigations of the mechanisms of lipid metabolism in human blood were then partially on the occasion of the deaths of hospital patients after intravenous administration of fat emulsions published. The investigation focused particularly on the products and LIPOMUL ABBOLIPID the North American pharmaceutical manufacturers UPJOHN and ABBOTT.

Between 1962 and 1976, aspects of the theme "Parenteral Nutrition" at numerous congresses of the International Society for Parenteral Nutrition ISPN and the European Society for Parenteral and Enteral Nutrition ESPEN in medical circles. As a topic repeatedly used most German Medical Association in particular the German Society for Nutritional Medicine DGEM for comments would be responsible for these products.

to illustrate to you my stance on the issue of existence and application of oil-containing infusion solutions, I would tell them also that to my letter dated in my 27th belong in October alleged objections to these products to less possible side effects of this agent as to the aspects of

1. basic incompatibility oily infusion solutions with added surface tension-reducing emulsifiers for the human blood and the
   

2. risk of misuse of these substances and the risk of application failures in connection with the administration of the substances to patients.

to already in my first written statement addressed fundamental incompatibility I want them using the following causal chain in a simplified form the main argumentation against the state on the market are oil-containing infusion media:

1. main component of blood is water

2. oil does not mix with water

3. The metabolism of autologous blood came into the transport medium fat is there in microscopic components of more than 1 diameter before Mykrometer

4. To reduce the size of the emulsion droplets of intravenously administered oil are the lipid infusion means oberflächenspannungsverringernde substances (emulsifiers) mixed

5. This oberflächenspannungsverringernden substances develop a similar oberflächenspannungsverringernde effect in human blood

6. This leads to damage of the blood plasma, the blood cells and clotting of the blood which can lead to so-called blood embolism

This , examined in the above-mentioned scientific publications effect of lipid infusion on human blood LIPOMUL is described as having "the blood plasma is transformed into a white, milky, creamy substance in the blood cells lose all coagulation ability. The human blood would thus be its main function as a transport medium for oxygen supply to the organs deprived.

The addition of smaller amounts of oil-containing infusion solutions by regulated, slow dropping of the substances from the blood infusion bottles in the human body could therefore have a certain Period to be absorbed. Fatal damage to the human body would be expected with this dosage form only after a certain period if they would not have the blood of biodegradable oil or the vehicle in the Kapillarendigungen the blood vessels of the supplied organs (especially in brain, lung, liver) accumulated and there would cause a disturbance of oxygen supply, which could lead to pulmonary or cerebral embolism.

latter is particularly associated with the technical information you mentioned is important that monitoring of patients particularly recommended in the initial phase of the lipid infusion . Similarly, the question of the non-degradable infusion Kapillarakkumulation shares for the above-mentioned clinical trials will play an important role, some of the subjects studied by taking blood and vital signs measurement only in the first 4 days after infusion administration. Neither blood nor vital signs were measured but the risk of onset of organ embolism by substance accumulation in the Kapillarendigungen show the blood vessel system. remain

to the above under 2 possible danger of abuse or misuse of substances to make the following comments:

During the search of my office CID research on the issue of lipid infusions, I was, according to informed by medical treatment personnel that cases known to his, which removes the infusion solution in the sterile dropper bottles and syringes had been transferred to administer the substance to patients by injection directly into the vein. That method are then made by the nursing staff as "at once" , "May in the clinic staff often overworked and be the nurse or nurses do not spend hours sat next to a patient in order to allow slow the oil-containing infusion solution according to the instructions for use for several hours to drip into the vein" . This administration takes shape, however, as stated above, blood embolism and immediately following the death of the patient .

If this is false, since, contrary to the manufacturer's instructions implemented application for lack of medical knowledge and intent, a potentially compromised patients "to be quickly send food" , then spoke a sometimes occurring application error of this kind does constitute a labeling requirement with appropriate warnings, as I they ask in my first letter to the BifAmMp.

If this misuse abuse, having regard to the products' impact and with deliberate intent to kill, it would actually also pose a risk to declare the "broth" as " Toxic or "not sufficient protection for hospital patients so treated.

would Expanding and finally, in this context to mention, that using the Level of West German nurses may well expect that the application of the risks of the oil-containing infusion solutions are known. However, can the total number of 20 different products indicate that the total volume produced in Germany, "oil-containing parenteral nutrient substance" not only hospital patients in the Federal Republic can be fed. That is, obviously, part of the manufactured products is exported to other countries or continents.

Not least for television news is the dramatic situation of refugees, particularly from African hunger crisis regions known. I believe it is important to make as a production country of so problematic and hazardous substance such as oil-based infusion nutrient solutions to proactively think about the possible errors that the unwitting because of poorly trained health workers were made, could occur misapplication. It would be only a matter of time before victims from these countries claim from the Federal Republic of Germany would comply.

Ultimately, there is also to countries in which the question of medical ethics is not considered high as here in Germany, which ultimately means that the improper application of the oil-containing infusate such as against political refugees, minorities, unpopular people, socially disadvantaged and marginalized by the production of the substance in Germany, responsible parties can not be excluded. I therefore consider a ban on production of lipid infusion solutions required.

It is left for me just to give you a very Merry Christmas and a Happy New Year.

Sincerely

Biol Peter Zanger
Research Director CID / CID-Verlag
Weilmünster, Wednesday, 21 December 2005

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